Synthesis of C2-Functionalized Pyrimidine Derivatives by Using Arynes and Dithiopyrimidines

C2-functionalized pyrimidine derivative is a family of important nitrogen heterocyclic compounds due to their unique structure and multiple reaction sites. In this work, a novel method for the synthesis of C2-functionalized pyrimidine derivatives through phenylalkynes and pyrimidine disulfides under ambient conditions is proposed. The reaction can be triggered by adding catalytic amounts of cesium fluoride, which is characterized by free-catalyst and special activator. Importantly, this reaction has good compatibility with substrates substituted by electron-donating and electron-withdrawing groups at C4. Density functional theory (DFT) calculations also indicates that the production of C2-functionalized pyrimidine derivatives is more favourable.     

嘧啶衍生物与人血清白蛋白的相互作用

在模拟生理条件下,运用荧光光谱、激光闪光光解(LFP)和分子对接等技术研究了8种具有抗肿瘤活性的嘧啶衍生物(PDs,其中PDs A 5-FU为成药,PDs B-H为实验室自制)与人血清白蛋白(HSA)的相互作用.利用Stern-Volmer方程和激光闪光光解技术分析了PDs对HSA的荧光猝灭机制,PDs A和B为静态猝灭,PDs G和H为动态猝灭.用双倒数曲线法得出5种PDs与HSA的结合常数Ka和结合位点数n,在测定条件下5种PDs与载体结合位点数均为1,且均以弱结合力结合,通过热力学参数ΔH,ΔS和ΔG推测出PDs B,C和E与HSA之间的作用力为静电作用力和疏水作用力,PDs A和D与HSA之间的作用力是氢键和范德华力,分子对接结果与其一致.根据F9rster非辐射能量转移理论(FRET)分析了HSA和PDs之间的结合距离(r),其结果均小于4 nm,符合能量转移理论.进一步利用同步荧光、三维荧光和圆二色光谱考察了PDs与HSA结合过程中HSA空间构象的变化,结果显示,仅PDs A和C对HSA的芳香族氨基酸周围的疏水性略有增强作用.体外实验结果表明,HSA可以作为优良的载体来运输和储存PDs A~E,这为嘧啶衍生物的后续研究提供了可参考的实验数据.     

Efficient synthesis of novel furo[2,3-d]pyrimidine derivatives under catalyst-free conditions

A series of furo[2,3-d]pyrimidine derivatives were synthesized via the [3+2] cyclization of pyrimidine-4,6-diol and a variety of nitroolefins at catalyst-free conditions. The reaction is easy to perform simply mixing inexpensive starting materials in water under conventional heating at 90 °C. The reaction proceeds at a fast speed within 1.5–2 h and gives the high biological and pharmacological active substituent furo[2,3-d]pyrimidine derivatives with good to high yields. Mechanism of formation of these furo[2,3-d]pyrimidine derivatives are also proposed.     

A Novel One‐Pot Method for the Synthesis of Pyrimidine Derivatives Using Ketene N,S‐Acetal with Aryl Aldehydes

A very simple and facile one‐pot method for the synthesis of pyrimidine derivatives is presented. In this method, 2‐aryl‐pyrimidine derivatives were prepared by the reaction of ketene N,S‐acetal 1 with commercially available aryl aldehydes by heating under solvent and catalyst‐free conditions. The synthesized pyrimidine derivatives showed blue‐green fluorescence in solid state.     

PHOTOCHEMICAL REACTIONS OF AROMATIC KETONES WITH NUCLEIC ACIDS AND THEIR COMPONENTS I—. PURINE AND PYRIMIDINE BASES AND NUCLEOSIDES*.

Abstract— The photochemical reactions of benzophenone and acetophenone with purine and pyrimidine derivatives in aqueous solutions have been investigated by flash photolysis and steady-state experiments. Upon excitation of these two ketones in aqueous solutions, two transient species are observed: molecules in their triplet state and ketyl radicals. The triplet state lifetimes are 65 μsec for benzophenone and 125 μsec for acetophenone. The ketyl radicals disappear by a second order reaction, controlled by diffusion. In the presence of pyrimidine derivatives, the triplet state is quenched and the ketyl radical concentration is decreased without any change in its kinetics of disappearance. Ketone molecules in their triplet state react with purine derivatives leading to an increase in the yield of ketyl radicals due to H-atom abstraction from the purines. Steady-state experiments show that benzophenone and acetophenone irradiated in aqueous solution at wavelengths longer than 290 nm undergo photochemical reactions. The rate of these photochemical reactions is increased in the presence of pyrimidine derivatives and even more in the presence of purine derivatives. Following energy transfer from the triplet state of benzophenone to diketopyrimidines, cyclobutane dimers are formed. The energy transfer rate decreases in the order orotic acid > thymine > uracil. Benzophenone molecules in their triplet state can also react chemically with pyrimidine derivatives to give addition photoproducts. All these results are discussed with respect to photosensitized reactions in nucleic acids involving ketones as sensitizers.     

One-pot and two-pot methods for chalcone derived pyrimidines synthesis and applications

Chalcone-derived pyrimidine is a well-known heterocyclic compound that is commonly present in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) bio-isosteres. Pyrimidine derivatives are effective in both the electronic industry and drug industries. This review highlights the synthesis of pyrimidines, namely mono-pyrimidine, bis-pyrimidine, fused pyrimidine, symmetric, and asymmetric pyrimidine via one-pot and two-pot methods. The one-pot method is the direct reaction of amino derivatives with aldehydes and acetophenones, whereas the two-pot method is frequently reported for the synthesis of chalcone before the cyclization to a pyrimidine. This review is important in organic synthesis, particularly in the heterocyclic field, regarding pyrimidines and their significance in therapeutic and electronic industries.     

Photoionization of DNA and RNA bases,nucleosides and nucleotides through a combination of one- and two-photon pathways upon 266 nm nanosecond laser excitation

The 266 nm nanosecond laser photolysis of various purine and pyrimidine derivatives results in their photoionization (PI) as one of the primary photochemical pathways. Electron photoejection occurs through a combination of one- and two-photon mechanisms. The PI values depend on the substituents attached to the chromophore of the base. The net PI of the purine bases at 266 nm are of the same order of magnitude (10(-2)) as those of the pyrimidine bases under similar experimental conditions. The monophotonic component is approximately one-third of the net PI yield of the bases. A nonrelaxed singlet excited state intermediate is tentatively proposed for this pathway. It is proposed that this state is significantly stabilized by water solvation, transforming it into a charge transfer to solvent state from which the hydrated electron evolves.     

Efficient Synthesis and Antimicrobial Evaluation of Acyclic Pyrimidine Nucleosides and Their Sulfanyl Analogs

Russian Journal of Organic Chemistry - A facile synthetic approach has been proposed for a new series of uracil acyclic nucleosides and their sulfanyl analogs via reaction of pyrimidine derivatives...     

Simple synthesis of some pentafluoropropenyl derivatives of pyrimidine and purine based on addition-elimination reaction

Various pentafluoropropenyl derivatives of pyrimidine and purine bases have been obtained in good to high yield. The procedure involves the reaction of appropriate lithium derivatives prepared from both electron-rich and electron-poor pyrimidines, with the hexafluoropropene at a low temperature, via an addition-elimination process. Organolithiums of pyrimidine and purine bases give addition-elimination products as E/Z mixtures, whereas the products of the reaction of lithium amide of protected inosine with hexafluoropropene contain traces of an addition product as well as the stable perfluoroenamine. The methodology proposed allows a series of perfluorovinyl nucleobases to be obtained quickly and conveniently.     

钯催化合成嘧啶核苷衍生物的研究进展

嘧啶核苷衍生物在药物化学、生物探针和核酸化学的研究中具有重要的作用, 金属催化碳碳的形成广泛应用于嘧啶核苷衍生物的合成. 综述了钯催化的Sonogashira反应、Stille反应、Heck反应以及Hiyama反应在嘧啶类核苷衍生物合成中的应用.     

Functional derivatives of thiophene

A method is proposed for the synthesis of 5-acylamino-2,3-dimethylthiophene-4-carbaldehydes and 5-acylamino-2,3-tetramethylenethiophene-4-carbaldehydes by the formylation of the corresponding thiophenes using the Vilsmeier reaction. From the formyl derivatives obtained, previously unaccessible derivatives of thieno[2,3-b]pyridine, thieno[2,3-d]pyrimidine, and thieno[3′,2′∶5,6]pyrido[2,3-d]-pyrimidine have been synthesized.     

Synthesis and antitumor activity of some nitrogen heterocycles bearing pyrimidine moiety

Synthesis of novel pyrimidine derivatives 4-16 was accomplished by heterocyclization of polarized system, for example, Chalcone. Claisen-Schmidt condensation of 2-acetyl naphthalene with 4-(N, N-dimethylaminobenzaldehyde) afforded chalcone 3 , which was utilized for synthesis various pyrimidine derivatives by treatment with urea, thiourea, and guandine hydrochloride in ethanolic sodium hydroxide solution. The reactivity of the synthesized pyrimidine derivatives towards different nucleophilic and electrophilic reagent were examined. The constructions of the newly synthesized pyrimidine derivatives were elucidated from their spectral and elemental analysis. All the synthesized compounds were tested in vitro for their anticancer activities against HePG-2 and MCF-7 cell lines. Some of them posses a wide range of pharmacological activity. Finally, a molecular docking study was conducted to reveal the probable interaction with the dihydrofolate reductase (DHFR) active site.     

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.     

Multiple tritium labelling of thymine and its derivatives

The paper deals with the synthesis of thymine and its derivatives carrying the label at C(6) in the pyrimidine in the methyl group and in deoxy-d-ribose. The molar activity of the preparations ranges from 0.85 to 4.94 PBq/mol. A procedure is proposed for obtaining tritium-labelled thymine compounds: nucleoside, nucleoside mono-, di- and triphosphates.     

5-vinyl pyrimidines. I. Synthesis

A total synthesis of 5-vinyl pyrimidine and some of its substituted derivatives is described. The following vinyl pyrimidines have been prepared: 5-vinyl pyrimidine, 5-vinyl-4,6-dimethoxy pyrimidine, 5-(α-bromo) vinyl-4,6-dimethoxy pyrimidine.     

The Use of 2‐Chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine as a Building Block in the Synthesis of Some New Heterocyclic Compounds

New approaches for the synthesis of some heterocyclic compounds, such as the pyridopyrimidodiazepine derivative 3 , pyrazolopyrido[1,2‐a]pyrimidine derivative 4 , tetrazolo[1.5‐a][1,8]naphthyridine derivative 9 , pyrazolylpyrido[1,2‐a]pyrimidine derivatives 10a , 10b , 12 , pyrrolopyrido[1,2‐a]pyrimidine derivatives 14a , 14b , 14c , 14d , and 16a , 16b , starting from 2‐chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine ( 1 ), are described.     

Synthesis of some new pyrimidine derivatives and evaluation of their anticancer and antibacterial activities

Starting from the reaction of ethyl cyanoacetate with thiourea and the appropriate aldehydes, a series of new pyrimidine derivatives were prepared. Ten selected pyrimidine derivatives were subjected to a screening system for the investigation of their antitumor potency against liver (HEPG2) cell line. The antitumor activity results indicated that most of the selected pyrimidine derivatives showed moderate growth inhibition activity against the tested cell line, but with varying intensities in comparison to the known anticancer drugs: 5-fluorouracil and doxorubicin. Some of the synthesized compounds were also tested for their antimicrobial activity against bacteria as well as fungal isolates.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

PHOTOCHEMICAL REACTIONS OF PYRIMIDINE DERIVATIVES WITH ACRYLONITRILE IN AQUEOUS SOLUTIONS

Abstract— Ultraviolet excitation of pyrimidine derivatives in aqueous solutions containing acrylonitrile can lead to polymerisation of acrylonitrile and/or photoaddition reactions of acrylonitrile and the pyrimidine. Polymerisation of acrylonitrile induced by excitation of orotic acid occurs even in aerated solutions and is very likely due to radicals derived from excited orotic acid molecuies. Using ¹⁴C-labelied orotic acid, the polymer is shown to contain the pyrimidine. With other pyrimidine derivatives, polymerisation is observed only in deaerated solutions and its low yield did not allow us to determine whether the polymerisation is induced by radicals or by photosensitisation. The role of the lowest excited singlet and triplet states of the pyrimidine derivatives in the photoaddition reaction is discussed. In the case of orotic acid, photoaddition is shown to proceed entirely by way of the triplet state.